This invention relates to novel pyrrolesulfonamide compounds. More specifically, this invention is concerned with pyrrolo[2,3-e][1,2]thiazine compounds, pyrrolo[3,4-e][1,2]thiazine compounds, pyrrolo[2,3-f][1,2]thiazepine compounds and pyrrolo[3,4-f][1,2]-thiazepine compounds, and salts thereof, said compounds and salts having strong xcex11-blocking action and serotonin-2 receptor antagonistic action and being useful as pharmaceuticals for the prevention or treatment of hypertension, heart failure, ischemic heart diseases such as angina pectoris, myocardial infarction and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans and Raynaud disease; their preparation processes; and pharmaceuticals containing them as effective ingredients.
Conventionally, many compounds are known as medicines which act on the circulatory system, including a variety of compounds developed as vasodilators.
Among such vasodilators, xcex11-blockers represented by prazosin are the subject of a great deal of active development work for their merits in that (1) their antihypertensive action is strong and positive, (2) they give no adverse effect to the metabolism of lipids and carbohydrates and (3) they can be easily used even for hypertensives suffering from complication. Examples of xcex11-blockers which are clinically used these days can include, in addition to prazosin, bunazosin, tetrazosin, urapidil and doxazosin. Further, medicines equipped with xcex11-blocking action and anti-serotonin action in combination have possibility to reduce side effects induced by hypotensive action based on the xcex11-blocking action, such as orthostatic hypotension and reflex tachycardia, and are hence expected to become superior hypertension therapeutics.
Further, hypertensives generally have potentiated platelet-aggregating ability and tend to form thrombi, so that they are considered to develop ischemic heart diseases or peripheral circulatory disturbances. As one of factors which take part in the formation of thrombi, serotonin is known. Serotonin is a compound contained abundantly in platelets, which are a blood component, and in a central nervous system, it acts as a neurotransmitter. In platelets, it is released upon stimulation by thromboxane A2, ADP, collagen or the like, and synergistically acts on release of various platelet aggregation factors through activation of serotonin-2 receptors in the platelets and vascular smooth muscle cells and also on vasoconstriction by norepinephrine through xcex11 receptors, thereby inducing strong platelet aggregation and vasoconstriction [P.M. Vanhoutte, xe2x80x9cJournal of Cardiovascular Pharmacologyxe2x80x9d, Vol. 17 (Supple. 5), S6-S12 (1991)].
Serotonin is also known to potentiate proliferation of vascular smooth muscle cells [S. Araki et al., xe2x80x9cAtherosclerosisxe2x80x9d, Vol. 83, pp.29-34(1990)]. It has been considered that, particularly when endothelial cells are injured as in arteriosclerosis or myocardial infarction, the vasoconstricting action and thrombus forming action of serotonin are exasperated, thereby reducing or even stopping blood supply to myocardial, cerebral and peripheral organs [P. Golino et al., xe2x80x9cThe New England Journal of Medicinexe2x80x9d, Vol. 324, No. 10, pp.641-648(1991), Y. Takiguchi et al., xe2x80x9cThrombosis and Haemostasisxe2x80x9d, Vol. 68(4), pp.460-463(1992), A. S. Weyrich et al., xe2x80x9cAmerican Journal of Physiologyxe2x80x9d, Vol. 263, H349-H358(1992)]. Being attracted by such actions of serotonin or serotonin-2 receptors, various attempts are now under way to use a serotonin-2 receptor antagonist as a pharmaceutical for ischemic diseases of the heart, the brain and peripheral tissues.
With the foregoing in view, medicines which have xcex11-blocking action and serotonin-2 receptor antagonistic action in combination are expected to have vasodilating action, anti-platelet action and vascular smooth muscle cell proliferation inhibitory action and are considered to become extremely effective medicines for the prevention and treatment of not only hypertension but also all circulator diseases, for example, heart failure, ischemic heart diseases such as angina pectoris, myocardial infarction and post-PTCA restenosis, cerebrovascular disturbances such as cerebral infarction and cerebral sequelae after subarachnoid hemorrhage, peripheral circulatory disturbances such as arteriosclerosis obliterans, thromboangiitis obliterans and Raynaud disease.
To date, several medicines have been reported to have xcex11-blocking action and serotonin-2 receptor antagonistic action in combination. They are however still accompanied with many problems to be improved in potency, selectivity to other receptors, toxicity, side effects and/or the like. There is accordingly an outstanding demand for the provision of still better compounds.
In view of the foregoing circumstances, the present inventors have proceeded with extensive research toward compounds which have strong xcex11-blocking action and serotonin-2 receptor antagonistic action in combination and also have low toxicity and less side effects and are thus useful for the prevention and treatment of all circulatory diseases such as hypertension, heart failure, ischemic heart diseases, cerebrovascular disturbances and peripheral circulatory disturbances. As a result, it has been found that pyrrolo[2,3-e]-thiazine compounds, pyrrolo[3,4-e]thiazine compounds, pyrrolo[2,3-f]thiazepine compounds and pyrrolo[3,4-f]-thiazepine compounds can satisfy such conditions.
Incidentally, pharmaceuticals having the pyrrolo[2,3-e]thiazine skeleton, pyrrolo[3,4-e]thiazine skeleton, pyrrolo[2,3-f]thiazepine skeleton or pyrrolo[3,4-f]thiazepine skeleton did not exist in the past, to say nothing of reports even on the synthesis of compounds having these skeletons.
The present invention has been completed based on the above described findings. A first object of the present invention is to provide a pyrrolesulfonamide compound or a salt thereof, said pyrrolesulfonamide compound being represented by the following formula (I): 
wherein
the ring P represented by 
xe2x80x83means a pyrrole ring represented by the following structure: 
xe2x80x83in which A represents a substituted or unsubstituted alkylene group, a substituted or unsubstituted alkenylene group or a substituted or unsubstituted alkynylene group; Y represents a group 
xe2x80x83in which W represents CH, Cxe2x95x90 or a nitrogen atom; and, when W represents CH, m stands for 0 or 1, B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group, a group xe2x80x94C(OH)R1xe2x80x94 in which R1 represents a substituted or unsubstituted aryl group, a group xe2x80x94CHR2xe2x80x94 in which R2 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group; when W represents Cxe2x95x90, m stands for 1, B represents a group 
xe2x80x83in which the double bond is coupled with W and R3 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; when W represents a nitrogen atom, m stands for 0 or 1, and B represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR4xe2x80x94 in which R4 represents a substituted or unsubstituted aryl group; E1 and E2 each independently represents a hydrogen atom or a lower alkyl group; and D represents a substituted or unsubstituted aromatic hydrocarbon group or a substituted or unsubstituted aromatic heterocyclic group;
l represents 0 or 1;
the dashed line indicates the presence or absence of a bond; and, when the bond indicated by the dashed line is present, Z2 is not present and Z1 represents a hydrogen atom but, when the bond indicated by the dashed line is absent, Z1 represents a hydrogen atom and Z2 represents a hydroxyl group; or Z1 and Z2 are combined together to represent an oxygen atom or a group NOR5 in which R5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group; and
R represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylalkyl group or a substituted or unsubstituted aralkyl group.
Another object of the present invention is to provide a preparation process of the pyrrolesulfonamide compound (I) or its salt.
A further object of the present invention is to provide a pharmaceutical which comprises the pyrrole-sulfonamide compound (I) or its pharmaceutically-acceptable salt as an effective ingredient and is usable for the treatment or the like of circulatory diseases.
In the pyrrolesulfonamide compound (I) of the present invention, preferred examples of the group R can include a hydrogen atom; linear or branched alkyl groups having 1-8 carbon atoms preferably, such as methyl, ethyl, n-propyl, isopropyl and n-pentyl; cycloalkyl groups having 3-8 carbon atoms, such as cyclopropyl, cyclopentyl and cyclohexyl; cycloalkylalkyl groups having 4-8 carbon atoms, such as cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl; and aralkyl groups having 7-22 carbon atoms, such as diphenylmethyl, benzyl and phenethyl. One or more hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy. Particularly preferred examples of the group R can include hydrogen atom, methyl and ethyl.
Further, preferred examples of the group Z1 and the group Z2 in the compound (I) according to the present invention can include the following combinations: when the bond indicated by the dashed line is present, Z2 is not present and Z1 represents a hydrogen atom; when the bond indicated by the dashed line is absent, Z1 represents a hydrogen atom and Z2 represents a hydroxyl group, or Z1 and Z2 are combined together to represent an oxygen atom or a group NOR5.
Preferred examples of R5 in the group NOR5 can include a hydrogen atom; linear or branched alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; and aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, and/or alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy. Of these, hydrogen atom and methyl group are particularly preferred.
Further, the ring P in the pyrrolesulfonamide compound (I) of the present invention represents one of the following pyrrole rings: 
wherein A and Y have the same meanings as defined above. Among these, particularly preferred are pyrrole rings represented by the following formula: 
wherein A and Y have the same meanings as defined above.
On the other hand, preferred examples of the group A can include linear or branched alkylene groups having 2-10 carbon atoms, such as ethylene, trimethylene, tetramethylene, pentamethylene and octamethylene; linear or branched alkenylene groups having 4-10 carbon atoms, such as 2-butenylene and 3-pentenylene; and linear or branched alkynylene groups having 4-10 carbon atoms, such as 2-butynylene and 3-pentynylene. One or more of the hydrogen atoms of each of these groups may be substituted by a like number of halogen atoms such as fluorine, chlorine and/or bromine atoms. Among the above groups, trimethylene, tetramethylene and pentamethylene are particularly preferred.
In the ring P, Y is a group 
wherein B, D, E1, E2, W and m have the same meanings as defined above. A group represented by the following formula: 
wherein E1, E2 and W have the same meanings as defined above, said group being included in the above group, is a heterocyclic group derived from piperidine or piperazine, and two or less of the hydrogen atoms on the ring may be substituted by a like number of alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl.
When the above group is a heterocyclic group derived from piperidine, m stands for 0 or 1 (with the proviso that m stands for 1 when W represents Cxe2x95x90), and B represents a carbonyl group, a sulfonyl group, an alkylene group (an alkylene group having 1-4 carbon atoms preferably, with a methylene group being particularly preferred), an alkenylene group (an alkenylene group having 2-5 carbon atoms preferably, with a 2-propenylene group being particularly preferred), a group xe2x80x94C(OH)R1xe2x80x94 in which R1 is an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, in which one or more of the hydrogen atoms may be substituted, a group xe2x80x94CHR2xe2x80x94 in which R2 is an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, in which one or more of the hydrogen atoms may be substituted, a group 
in which the double bond is coupled with W, R3 represents an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl, or an aralkyl group having 7-22 carbon atoms, such as benzyl or phenethyl, and these groups may be in substituted forms, or a cyclic or acyclic acetal group in which one or more of the hydrogen atoms may be substituted.
Exemplary cyclic or acyclic acetal groups include: 
In the above-described definition of B, preferred examples of substituents on the groups R1, R2 and R3 can include one or more alkyl groups having 1-4 carbon atoms, such as methyl and ethyl; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; halogen atoms such as fluorine atoms, chlorine atoms and bromine atoms; alkoxy groups having 1-4 carbon atoms, such as methoxy and ethoxy; hydroxyl groups; cyano groups; and nitro groups.
Further, illustrative of substituents on the cyclic or acyclic acetal are halogen atoms such as fluorine atoms, chlorine atoms, and bromine atoms; alkyl groups having 1-4 carbon atoms, such as methyl and ethyl; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl; and alkylidene groups having 1-4 carbon atoms preferably, such as methylidene and ethylidene.
As a particularly preferred example of B, a carbonyl group can be mentioned.
When the heterocyclic group is a group derived from piperazine, m stands for 0 or 1 (preferably 0), and B represents a carbonyl group, a sulfonyl group, an alkylene group (preferably, an alkylene group having 1-4 carbon atoms, with a methylene group being particularly preferred), an alkenylene group (preferably, an alkenylene group having 3-6 carbon atoms, with a 2-propenylene group being particularly preferred), a group xe2x80x94CHR4xe2x80x94 in which R4 represents an aryl group having 6-14 carbon atoms, such as phenyl or naphthyl.
The above-described R4 may be substituted further, for example, by one or more of halogen atoms such as fluorine, chlorine and/or bromine, alkyl groups having 1-4 carbon atoms preferably, such as methyl and/or ethyl, alkoxy groups having 1-4 carbon atoms preferably, such as methoxy and/or ethoxy, nitro groups, cyano groups, carboxyl groups, and/or hydroxyl groups.
As a preferred example of the above-described B, a substituted or unsubstituted phenylmethylene group can be mentioned.
Preferred examples of group D can include aromatic hydrocarbon groups having 6-28 carbon atoms preferably, such as a phenyl group in which one or more of the hydrogen atoms may be substituted and a naphthyl group in which one or more of the hydrogen atoms may be substituted.
Other preferred examples of D can include aromatic heterocyclic groups, preferably those each of which is monocyclic or bicyclic and contains three or less hetero atoms, such as pyridyl, pyrimidinyl, benzisothiazolyl, benzisoxazolyl, indazolyl and indolyl groups in which one or more of hydrogen atoms may be substituted. Examples of the hetero atoms can include oxygen, sulfur and nitrogen atoms.
Examples of the substituents for the above aromatic hydrocarbon group or aromatic heterocyclic group can include halogen atoms such as fluorine, chlorine and bromine; alkyl groups having 1-4 carbon atoms preferably, such as methyl and ethyl; alkoxyl groups having 1-4 carbon atoms preferably, such as methoxy and ethoxy; aryl groups having 6-14 carbon atoms, such as phenyl and naphthyl; aralkyl groups having 7-22 carbon atoms, such as benzyl and phenethyl; aralkyloxy groups having 7-22 carbon atoms preferably, such as benzyloxy; cyano groups; nitro groups; carboxyl groups; alkoxycarbonyl groups (with an alcohol moiety thereof having 1-6 carbon atoms preferably); lower alkylsulfonylamino groups (with an alkyl moiety thereof having 1-4 carbon atoms preferably); carbamoyl groups; and hydroxyl groups.
Among these examples of group D, preferred ones can include phenyl groups which may be unsubstituted or substituted by one or more of halogen atoms, alkoxy groups and/or hydroxyl groups; benzisothiazolyl groups which may be unsubstituted or substituted by one or more halogen atoms; benzisoxazolyl groups which may be unsubstituted or substituted by one or more halogen atoms; and indazolyl groups which may be unsubstituted or substituted by one or more halogen atoms. Particularly preferred are an unsubstituted phenyl group; and phenyl groups substituted by one or more of fluorine atoms, methoxy groups and/or hydroxyl groups.
Many of the compounds (I) according to the present invention have isomers. It is to be noted that these isomers and mixtures thereof are all embraced by the present invention.
The pyrrolesulfonamide compounds (I) according to the present invention can be prepared by various processes. It is however preferred to prepare each of them, for example, by using a pyrrolesulfonamide compound (II) or (IIxe2x80x2), which is available by Process 1 to be described below, and following any one of the processes to be described as Process 2 onwards.
Pyrrolesulfonamide compounds (II) and (IIxe2x80x2) useful as starting materials can be synthesized, for example, by the following process:
Compounds represented by the formula (II) and (IIxe2x80x2) can be obtained in accordance with the following reaction scheme, namely, by converting pyrrole-3-sulfonic acid or a salt thereof represented by the formula (XIII) into a pyrrole-3-sulfonyl halide represented by the formula (XIV), reacting xcex1-aminoacetic acid, xcex2-aminopropionic acid or a derivative thereof (XV) or an organic or inorganic acid salt thereof with the compound (XIV) and, if necessary, conducting deprotection to obtain a compound represented by the formula (XVI) and then subjecting the thus-obtained compound to a ring-closing reaction. 
xe2x80x83wherein M represents a hydrogen ion, an alkali metal ion, an alkaline earth metal ion or a quaternary ammonium ion, and p stands for 1 when M represents a hydrogen ion, an alkali metal ion or a quaternary ammonium ion or p stands for 2 when M represents an alkaline earth metal ion, Xxe2x80x3 represents a chlorine atom or a bromine atom, R6 represents a hydrogen atom or a carboxyl-protecting group, and R and l have the same meanings as defined above.
Illustrative of M in the compound represented by the formula (XIII) in the above scheme are hydrogen ion; alkali metal ions such as sodium ion and potassium ion; alkaline earth metal ions such as barium ion; and quaternary ammonium ions such as pyridinium ion. The compound represented by the formula (XIII) can be obtained in accordance with the following formula, namely, by causing a sulfonating agent such as sulfur trioxide.pyridine complex to act on pyrrole (XVII) and, if necessary, treating the resultant compound with an acid such as hydrochloric acid or sulfuric acid or a base such as sodium hydroxide, sodium carbonate, sodium hydrogencarbonate or barium hydroxide. 
wherein M and p have the same meanings as defined above.
Further, the compound (XIV) can be obtained by causing phosphorus pentachloride or phosphorus pentabromide to act on the compound (XIII) in a solvent which does not take part in the reaction, such as ethyl ether or toluene. In addition, as the carboxyl-protecting group represented by the group R6 in the compound (XV), it is possible to use, in addition to lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl and aralkyl groups having 7-20 carbon atoms, such as benzyl and 9-anthrylmethyl, conventional protecting groups such as those described in T. W. Greene: xe2x80x9cProtective Groups in organic Synthesisxe2x80x9d (John Wiley and Sons, Inc.) and the like.
Further, as an illustrative synthesis process of the compound (XVI), a process can be mentioned in which a base is added to the compound (XIV), as needed, and xcex1-aminoacetic acid, xcex2-aminopropionic acid or a derivative thereof (XV) or an organic or inorganic acid salt thereof is caused to act. Usable examples of the base can include organic bases such as triethylamine and pyridine, and inorganic bases such as sodium hydrogen-carbonate, potassium carbonate and sodium hydroxide.
The compound (XVI) so obtained is subjected to a cyclizing reaction, optionally after removing the protecting group by virtue of a suitable method such as the action of an acid or a base, or catalytic reduction. This cyclizing reaction is conducted by treating the compound (XVI) together with an organic acid such as methanesulfonic acid, an inorganic acid such as sulfuric acid or polyphosphoric acid or a mixture of such an organic or inorganic acid and phosphorus pentoxide at room temperature to 170xc2x0 C., preferably at 80-120xc2x0 C. In this case, a solvent which does not take part in the reaction may be added as needed.
Further, the cyclizing reaction can also be practiced by, optionally after addition of a catalyst such as dimethylformamide to the compound (XVI) in which R6 is a hydrogen atom, treating the compound with oxalyl chloride, thionyl chloride, thionyl bromide, oxalyl bromide, phosgene, phosphorus trichloride, phosphorus tribromide, phosphoryl chloride, phosphoryl bromide or the like to convert it into its corresponding acid halide and then treating the acid halide at xe2x88x9220xc2x0 C. to reflux temperature in the presence of a Lewis acid such as aluminum chloride, aluminum bromide, boron trifluoride-ether complex or tin tetrachloride in a solvent such as dichloromethane, 1,2-dichloroethane or nitromethane. In the above-described reactions, the compound (II) and the compound (IIxe2x80x2) can be formed at varied ratios by changing the reaction conditions.
Among the pyrrolesulfonamide compounds (I), compounds (Ia) and (Iaxe2x80x2) in each of which Z1 and Z2 are combined together to represent an oxygen atom can be synthesized, for example, by any one of the following processes.
Each compound (Ia) or compound (Iaxe2x80x2) can be obtained in accordance with the following reaction scheme, namely, by reacting a compound represented by the formula (II) or (IIxe2x80x2) with a compound represented by the formula (III) to convert the compound (II) or (IIxe2x80x2) into a compound represented by the formula (IV) or (IVxe2x80x2) and then reacting a nitrogen-containing compound represented by the formula (V) or a salt thereof with the compound (IV) or (IVxe2x80x2). 
wherein A, R, Y and l have the same meanings as defined above, and X and Xxe2x80x2 represent the same or different eliminative groups.
In the above-described reaction, the conversion from the compound (II) or (IIxe2x80x2) into the compound (IV) or (IVxe2x80x2) can be effected by treating the compound (II) or (IIxe2x80x2) with an organic or inorganic base and then reacting the compound (III), or by causing the compound (III) to act on the compound (II) or (IIxe2x80x2) in the presence of such a base.
The groups X and Xxe2x80x2 in the compound (III) are eliminative groups, and illustrative can be halogen atoms such as chlorine and bromine, alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as p-toluenesulfonyloxy.
Exemplary inorganic bases or organic bases can include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, sodium ethoxide, and potassium t-butoxide. Further, illustrative of a solvent usable in this reaction are acetone, 2-butanone, acetonitrile, dimethyl sulfoxide, dioxane, and toluene. The reaction can be conducted at xe2x88x9220xc2x0 C. to reflux temperature.
To prepare the compound (Ia) or (Iaxe2x80x2) from the thus-obtained compound (IV) or (IVxe2x80x2), it is only necessary to react the compound (IV) or (IVxe2x80x2) and the nitrogen-containing compound (V) or an organic acid salt or inorganic acid salt thereof, optionally together with an organic base such as triethylamine, pyridine, collidine or potassium t-butoxide or an inorganic base such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide or sodium hydroxide and optionally with the addition of an alkali iodide such as potassium iodide or sodium iodide, in a solventless manner or in the above-exemplified solvent or a solvent such as methanol or ethanol at room temperature to 150xc2x0 C.
Examples of the nitrogen-containing compound (V) can include 1-phenylpiperazine, 1-(2-fluorophenyl)piperazine, 1-(3-fluorophenyl)piperazine, 1-(4-fluorophenyl)piperazine, 1-(4-hydroxyphenyl)piperazine, 1-(2-chlorophenyl)piperazine, 1-(3-chlorophenyl)piperazine, 1-(4-chlorophenyl)piperazine, 1-(2-methoxyphenyl)piperazine, 1-(3-methoxyphenyl)piperazine, 1-(4-methoxyphenyl)piperazine, 1-(4-methanesulfonamidophenyl)piperazine, 1-(4-cyanophenyl)piperazine, 1-(4-carbamoylphenyl)piperazine, 1-(4-methoxycarbonylphenyl)piperazine, 1-(2-pyridyl)piperazine, 1-(2-pyrimidinyl)piperazine, 1-benzylpiperazine, 1-diphenylmethylpiperazine, 1-cinnamylpiperazine, 1-benzoylpiperazine, 1-(4-benzyloxybenzoyl)piperazine, 1-(4-hydroxybenzoyl)piperazine, 1-(2-furoyl)piperazine, 1-(1,2-benzisoxazol-3-yl)piperazine, 1-(1,2-benzisothiazol-3-yl)piperazine, 4-phenylpiperidine, 4-benzylpiperidine, xcex1,xcex1-bis(4-fluorophenyl)-4-piperidine-methanol, 4-(4-fluorobenzoyl)piperidine, 4-benzoylpiperidine, 4-(4-methoxybenzoyl)piperidine, 4-(4-chlorobenzoyl)piperidine, 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine, 4-(6-fluoro-1,2-benzisothiazol-3-yl)piperidine, 4-(6-fluoro-1H-indazol-3-yl)piperidine, 4-[(4-fluorophenyl)sulfonyl]piperidine, 4-[bis(4-fluorophenyl)methylene]piperidine, and 4-(4-fluorobenzoyl)piperidine ethylene acetal. These compounds are either known in the art or readily available by processes known per se in the art or by processes similar to such known processes.
Further, the compound (Ia) or (Iaxe2x80x2) can also be obtained by causing a nitrogen-containing compound represented by the formula (VI) to act on the compound represented by the formula (II) or (IIxe2x80x2) in accordance with the following reaction formula: 
wherein A, R, X, Y and l have the same meanings as defined above.
The conversion from the compound (II) or (IIxe2x80x2) into the compound (Ia) or (Iaxe2x80x2) is conducted by causing the compound (VI) to act either after treatment of the compound (II) or (IIxe2x80x2) with an inorganic base or an organic base or in the presence of an inorganic base or an organic base. Reaction conditions are similar to those employed upon conversion from the compound (II) into the compound (IV) and described above under Process (a) of Process 2. Further, the compound (VI) can be synthesized by reacting the compound (III) with the compound (V) in a manner known per se in the art.
Among the pyrrolesulfonamide compounds (I), the compounds (Ic) and (Icxe2x80x2) and the compounds (Ie) and (Iexe2x80x2) in each of which Z1 and Z2 are combined together to represent a group NOR5 can each be synthesized by any one of the following processes.
Each compound (Ie) or (Iexe2x80x2) is obtained in accordance with the following reaction scheme, namely, by causing hydroxylamine or a derivative thereof (VII) or a salt thereof to act on a compound represented by the formula (IV) or (IVxe2x80x2) and then causing a nitrogen-containing compound (V) to act. 
wherein A, R, R5, X, Y and l have the same meanings as defined above.
The reaction between the compound (IV) or (IVxe2x80x2) and the hydroxylamine or its derivative (VII) is effected, if necessary, in the presence of an organic base such as pyridine, triethylamine, collidine or sodium acetate or an inorganic base such as potassium carbonate or sodium hydroxide. The hydroxylamine or its derivative (VII) may also be used in the form of an organic acid salt or an inorganic acid salt.
The reaction is conducted at 0xc2x0 C. to reflux temperature, preferably 0xc2x0 C.-100xc2x0 C. by adding a suitable solvent, for example, methanol, ethanol, propanol, tetrahydrofuran, dimethylformamide or dimethylsulfoxide as needed.
Further, the conversion from the thus-obtained compound (VIII) or (VIIIxe2x80x2) into the compound (Ie) or (Iexe2x80x2) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) shown above under Process (a) of Process 2.
Each compound (Ic) or (Icxe2x80x2) is obtained by causing hydroxylamine or its derivative (VII) or a salt thereof to act on a compound (Ib) or (Ibxe2x80x2) in accordance with the following reaction formula. 
wherein Yxe2x80x2 represents a group 
in which when W represents CH, Bxe2x80x2 represents a sulfonyl group, an alkylene group, an alkenylene group, a group xe2x80x94C(OH)R1xe2x80x94 in which R1 represents a substituted or unsubstituted aryl group, a group xe2x80x94CHR2xe2x80x94 in which R2 represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted cyclic or acyclic acetal group; when W represents Cxe2x95x90, Bxe2x80x2 represents a group 
in which the double bond is coupled with W and R3 represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aralkyl group; when W represents a nitrogen atom, Bxe2x80x2 represents a carbonyl group, a sulfonyl group, an alkylene group, an alkenylene group or a group xe2x80x94CHR4xe2x80x94 in which R4 represents a substituted or unsubstituted aryl group; and D, E1, E2 and m have the same meanings as defined above, and A, R, R5 and l have the same meanings as defined above.
The conversion from the compound (Ib) or (Ibxe2x80x2) into the compound (Ic) or (Icxe2x80x2) can be effected under similar conditions as the conversion from the compound (IV) into the compound (VIII) shown above under Process (a) of Process 3.
Among the pyrrolesulfonamide compounds (I), the compounds (Id) and (Idxe2x80x2) and the compounds (If) and (Ifxe2x80x2) in each of which Z1 represents a hydrogen atom and Z2 represents a hydroxyl group can each be synthesized by any one of the following processes.
Each compound (If) or (Ifxe2x80x2) is obtained in accordance with the following reaction scheme, namely, by reducing a compound represented by the formula (IV) or (IVxe2x80x2) and then causing a nitrogen-containing compound (V) to act. 
wherein A, R, X, Y and l have the same meanings as defined above.
The conversion from the compound (IV) or (IVxe2x80x2) into the compound (IX) or (IXxe2x80x2) is conducted by treating the compound represented by the formula (IV) or (IVxe2x80x2) with a reducing agent such as sodium borohydride, potassium borohydride or sodium cyanoborohydride at xe2x88x9278xc2x0 C. to reflux temperature, preferably xe2x88x9220xc2x0 C. to room temperature in a conventionally used solvent.
The conversion from the compound (IX) or (IXxe2x80x2) into the compound (If) or (Ifxe2x80x2) can be effected under similar conditions as the conversion from the compound (IV) into the compound (Ia) shown above under Process (a) of Process 2.
Each compound (Id) or (Idxe2x80x2) is obtained by reducing a compound represented by the formula (Ib) or (Ibxe2x80x2) in accordance with the following reaction formula. 
wherein A, R, Yxe2x80x2 and l have the same meanings as defined above.
The conversion from the compound (Ib) or (Ibxe2x80x2) into the compound (Id) or (Idxe2x80x2) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (IX) shown above under Process (a) of Process 4.
Among the pyrrolesulfonamide compounds (I), the compounds (Ig) and (Igxe2x80x2) in each of which the bond indicated by the dashed line is present and Z1 represents a hydrogen atom can be synthesized by any one of the following processes.
Each compound (Ig) or (Igxe2x80x2) is obtained in accordance with the following reaction scheme, namely, by subjecting a compound represented by the formula (IX) or (IXxe2x80x2) to a dehydration reaction to obtain a compound represented by the formula (X) or (Xxe2x80x2) and then causing a nitrogen-containing compound (V) to act on the compound (X) or (Xxe2x80x2). 
wherein A, R, X, Y and l have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (IX) or (IXxe2x80x2) into the compound (X) or (Xxe2x80x2) can be effected by treating the compound (IX) or (IXxe2x80x2) with an acid such as hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at xe2x88x9220xc2x0 C. to room temperature in a solvent such as water, methanol, ethanol, ethyl acetate, chloroform or toluene.
As an alternative, the conversion into the compound (X) or (Xxe2x80x2) can also be effected by causing methanesulfonyl chloride, p-toluenesulfonyl chloride, phosphorus trichloride, phosphorus oxychloride, thionyl chloride or the like and a base such as triethylamine, pyridine or collidine to act on the compound (IX) or (IXxe2x80x2) in a solvent such as dichloromethane, chloroform or toluene.
The conversion from the compound (X) or (Xxe2x80x2) into the compound (Ig) or (Igxe2x80x2) can be effected under similar conditions as in the conversion from the compound (IV) into the compound (Ia) described above under Process (a) of Process 2.
Each compound (Ig) or (Igxe2x80x2) is obtained by subjecting a compound represented by the formula (If) or (Ifxe2x80x2) to a dehydration reaction in accordance with the following reaction formula: 
wherein A, R, Y and l have the same meanings as defined above.
In the above-described reaction, the conversion from the compound (If) or (Ifxe2x80x2) into the compound (Ig) or (Igxe2x80x2) can be effected under similar conditions as in the conversion from the compound (IX) into the compound (X) described above under Process (a) of Process 5.
If necessary, the compounds (I) of the present invention obtained according to the above-described processes can each be reacted with one of various acids to convert the compound into its salt. Then, the resulting salt can be purified by a method such as recrystallization or column chromatography.
Exemplary acids usable for the conversion of the pyrrolesulfonamide compounds (I) into their salts can include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid and hydrobromic acid; and organic acids such as maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid and tannic acid.
Further, the compounds (I) according to the present invention include those containing asymmetric centers. Each racemic mixture can be isolated by one or more of various methods, whereby a single optically-active substance can be obtained. Usable methods include, for example:
(1) Isolation by an optically active column.
(2) Isolation by recrystallization subsequent to conversion into a salt with an optically active acid.
(3) Isolation by an enzyme reaction.
(4) Isolation by a combination of the above methods (1) to (3).
The pyrrolesulfonamide compounds (I) and their salts, which are obtained as described above, have strong serotonin-2 blocking action as will be demonstrated in tests to be described subsequently herein. Moreover, the compounds (I) according to the present invention have also been found to include those also having xcex11-blocking action. From the results of toxicity tests, the compounds (I) and salt thereof according to the present invention have also been found to possess high safety. The compounds and salt thereof according to the present invention can therefore be used as pharmaceuticals for the treatment of circulatory diseases such as ischemic heart diseases, cerebrovascular disturbances, peripheral circulatory disturbances and hypertension.
When the pyrrolesulfonamide compounds (I) according to this invention are used as pharmaceuticals, they can be administered in an effective dose as they are. As an alternative, they can also be formulated into various preparation forms by known methods and then administered.
Exemplary preparation forms as medicines include orally administrable preparation forms such as tablets, capsules and syrups as well as parenterally administrable preparation forms such as injections and suppositories. Whichever preparation form is used, a known liquid or solid extender or carrier usable for the formulation of the preparation form can be employed.
Examples of such extender or carrier include polyvinylpyrrolidone, arabic gum, gelatin, sorbit, cyclodextrin, tragacanth gum, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol, silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethylcellulose, sodium laurylsulfate, water, ethanol, glycerin, mannitol, syrup, and the like.
When the compounds (I) according to the present invention are used as pharmaceuticals, their dose varies depending on the administration purpose, the age, body weight, conditions, etc. of the patient to be administered. In oral administration, the daily dose may generally be about 0.01-1,000 mg.
The present invention will next be described in further detail by the following examples and tests. It is however to be noted that the present invention is by no means limited to the following examples.